Compounds and methods of treating cancers

Abstract

This disclosure relates to GSPT1 degrader compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising such compounds or salts, and methods of making and using the compounds or salts for the treatment of certain diseases. The disclosure also relates to methods for identifying such compounds.

What is claimed is: 
     
         1 . A compound of Formula (A): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         W is hydrogen or fluorine; 
         Z is absent, —NR 1a —, or —O—; wherein R 1a  is hydrogen or C 1 -C 8  alkyl; 
         L is an optionally substituted C 1 -C 10  alkylene or optionally substituted C 1 -C 10  heteroalkylene, or 
         L is 
       
       
         
           
           
               
               
           
         
          wherein: 
         Ring B is an optionally substituted 3-7 membered carbocyclyl or optionally substituted 4-7 membered heterocyclyl; 
         L 1  is absent, or an optionally substituted C 1 -C 10  alkylene or optionally substituted C 1 -C 10  heteroalkylene; 
         L 2  is absent, or an optionally substituted C 1 -C 10  alkylene, optionally substituted C 2 -C 10  alkenylene, optionally substituted C 2 -C 10  alkynylene, or optionally substituted C 1 -C 10  heteroalkylene; 
         R 1  is absent or oxo (═O); 
         R 2  and R 4  are each independently hydrogen, halogen, CN, OR 5 , N(R 5 )R 6 , C(O)R 5 , C(O)OR 5 , C(O)N(R 5 )R 6 , optionally substituted C 1 -C 8  alkyl, optionally substituted C 1 -C 8  alkoxy, optionally substituted C 1 -C 8  alkylamino, optionally substituted C 1 -C 8  haloalkyl, optionally substituted C 1 -C 8  heteroalkyl, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl; 
         R 3  is hydrogen, halogen, CN, OR 5 , N(R 5 )R 6 , C(O)R 5 , C(O)OR 5 , C(O)N(R 5 )R 6 , optionally substituted C 1 -C 8  alkyl, optionally substituted C 1 -C 8  alkoxy, optionally substituted C 1 -C 8  alkylamino, optionally substituted C 1 -C 8  haloalkyl, optionally substituted C 1 -C 8  heteroalkyl, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl; or 
         R 2  and R 3  or R 3  and R 4  are taken together to form an optionally substituted 3-7 membered partially saturated or unsaturated carbocyclyl, optionally substituted 4-7 membered partially saturated or unsaturated heterocyclyl, optionally substituted phenyl, or optionally substituted 5-6 membered heteroaryl ring; 
         each R 5  and R 6  is independently hydrogen, optionally substituted C 1 -C 8  alkyl, optionally substituted C 2 -C 8  alkenyl, optionally substituted C 2 -C 8  alkynyl, optionally substituted C 1 -C 8  haloalkyl, optionally substituted C 1 -C 8  heteroalkyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclylC 1 -C 8 alkyl, optionally substituted 3-10 membered heterocyclylC 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl; or 
         R 5  and R 6  together with the atom(s) to which they are attached optionally form an optionally substituted 4-7 membered heterocyclyl or optionally substituted 5-6 membered heteroaryl ring. 
       
     
     
         2 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Z is absent, —NR 1a —, or —O—; wherein R 1a  is hydrogen or C 1 -C 8  alkyl; 
         L is an optionally substituted C 1 -C 10  alkylene or optionally substituted C 1 -C 10  heteroalkylene, or 
         L is 
       
       
         
           
           
               
               
           
         
          wherein: 
         Ring B is an optionally substituted 3-7 membered carbocyclyl or optionally substituted 4-7 membered heterocyclyl; 
         L 1  is absent, or an optionally substituted C 1 -C 10  alkylene or optionally substituted C 1 -C 10  heteroalkylene; 
         L 2  is absent, or an optionally substituted C 1 -C 10  alkylene, optionally substituted C 2 -C 10  alkenylene, optionally substituted C 2 -C 10  alkynylene, or optionally substituted C 1 -C 10  heteroalkylene; 
         R 1  is absent or oxo (═O); 
         R 2  and R 4  are each independently hydrogen, halogen, CN, OR 5 , N(R 5 )R 6 , C(O)R 5 , C(O)OR 5 , C(O)N(R 5 )R 6 , optionally substituted C 1 -C 8  alkyl, optionally substituted C 1 -C 8  alkoxy, optionally substituted C 1 -C 8  alkylamino, optionally substituted C 1 -C 8  haloalkyl, optionally substituted C 1 -C 8  heteroalkyl, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl; 
         R 3  is hydrogen, halogen, CN, OR 5 , N(R 5 )R 6 , C(O)R 5 , C(O)OR 5 , C(O)N(R 5 )R 6 , optionally substituted C 1 -C 8  alkyl, optionally substituted C 1 -C 8  alkoxy, optionally substituted C 1 -C 8  alkylamino, optionally substituted C 1 -C 8  haloalkyl, optionally substituted C 1 -C 8  heteroalkyl, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl; or 
         R 2  and R 3  or R 3  and R 4  are taken together to form an optionally substituted partially unsaturated 3-7 membered carbocyclyl, optionally substituted partially unsaturated 4-7 membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5-6 membered heteroaryl ring; 
         each R 5  and R 6  is independently hydrogen, optionally substituted C 1 -C 8  alkyl, optionally substituted C 2 -C 8  alkenyl, optionally substituted C 2 -C 8  alkynyl, optionally substituted C 1 -C 8  haloalkyl, optionally substituted C 1 -C 8  heteroalkyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclylC 1 -C 8 alkyl, optionally substituted 3-10 membered heterocyclylC 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl; or 
         R 5  and R 6  together with the atom(s) to which they are attached optionally form an optionally substituted 4-7 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl ring. 
       
     
     
         3 . The compound of  claim 1 or claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 2  and R 3  are taken together to form an optionally substituted phenyl or optionally substituted 5-6 membered heteroaryl ring. 
     
     
         4 . The compound of  claim 1 or claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 3  and R 4  are taken together to form an optionally substituted phenyl or optionally substituted 5-6 membered heteroaryl ring. 
     
     
         5 . The compound of  claim 1, 2, or 4 , wherein the compound has the structure of Formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Ring A is a phenyl or 5-6 membered heteroaryl; 
         each R 11  is independently hydrogen, halogen, CN, NO 2 , OR 5 , SR 5 , N(R 5 )R 6 , C(O)R 5 , C(O)OR 5 , C(O)N(R 5 )R 6 , optionally substituted C 1 -C 8  alkyl, optionally substituted C 1 -C 8  haloalkyl, optionally substituted C 1 -C 8  heteroalkyl, optionally substituted C 1 -C 8  alkoxy, optionally substituted C 1 -C 8  alkylamino, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl; and 
         p 1  is 0, 1, 2, 3, or 4. 
       
     
     
         6 . The compound of  claim 5 , or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, pyridinyl, or triazinyl. 
     
     
         7 . The compound of  claim 5 , wherein the compound has the structure of Formula (II-A): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X 1 , X 2  and X 3  are each independently CR 11  or N. 
       
     
     
         8 . The compound of  claim 7 , or a pharmaceutically acceptable salt thereof, wherein X 1  is N; and X 2  and X 3  are each independently CR 11 . 
     
     
         9 . The compound of  claim 7 , or a pharmaceutically acceptable salt thereof, wherein X 1  and X 2  are each N; and X 3  is CR 11 . 
     
     
         10 . The compound of  claim 7 , or a pharmaceutically acceptable salt thereof, wherein X 1  and X 3  are each N; and X 2  is CR 11 . 
     
     
         11 . The compound of  claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein R 4  is hydrogen; and R 3  is N(R 5 )R 6 , optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl. 
     
     
         12 . The compound of  claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 3  is optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl. 
     
     
         13 . The compound of any one of  claims 1, 2, 11 or 12 , wherein the compound has the structure of Formula (III): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X 4 , X 5  and X 6  are each independently CR 8  or N; 
         each R 8  is independently hydrogen, halogen, CN, NO 2 , OR 5 , SR 5 , N(R 5 )R 6 , C(O)R 5 , C(O)OR 5 , C(O)N(R 5 )R 6 , optionally substituted C 1 -C 8  alkyl, optionally substituted C 1 -C 8  haloalkyl, optionally substituted C 1 -C 8  heteroalkyl, optionally substituted C 1 -C 8  alkoxy, optionally substituted C 1 -C 8  alkylamino, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl; or 
         two R 8  on adjacent carbon atoms are taken together to form an optionally substituted partially unsaturated 3-7 membered carbocyclyl, optionally substituted partially unsaturated 4-7 membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5-6 membered heteroaryl ring; and 
         p 2  is 0, 1, 2, 3, 4, or 5. 
       
     
     
         14 . The compound of  claim 13 , or a pharmaceutically acceptable salt thereof, wherein X 4 , X 5  and X 6  are each independently CR 8 . 
     
     
         15 . The compound of  claim 13 , or a pharmaceutically acceptable salt thereof, wherein X 4  is N; and X 5  and X 6  are each independently CR 8 . 
     
     
         16 . The compound of any one of  claims 13 to 15 , or a pharmaceutically acceptable salt thereof, wherein each R 8  is independently hydrogen, halogen, or optionally substituted C 1 -C 8  alkyl. 
     
     
         17 . The compound of any one of  claims 1, 2, 11 or 12 , wherein the compound has the structure of Formula (IV): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X 4  is CR 8a  or N; 
         X 5  is CR 8b  or N; 
         X 6  is CR 8d  or N; 
         R 8a , R 8b , R 8c , R 8d , and R 8e  are each independently hydrogen, halogen, CN, NO 2 , OR 5 , SR 5 , N(R 5 )R 6 , C(O)R 5 , C(O)OR 5 , C(O)N(R 5 )R 6 , optionally substituted C 1 -C 8  alkyl, optionally substituted C 1 -C 8  haloalkyl, optionally substituted C 1 -C 8  heteroalkyl, optionally substituted C 1 -C 8  alkoxy, optionally substituted C 1 -C 8  alkylamino, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl; or 
         R 8a  and R 8b , R 8b  and R 8c , R 8c  and R 8d , or R 8d  and R 8e  are taken together with the atoms to which they are attached to form an optionally substituted 3-7 membered carbocyclyl, optionally substituted 4-7 membered heterocyclyl, optionally substituted 6 membered aryl, or optionally substituted 5-6 membered heteroaryl ring. 
       
     
     
         18 . The compound of  claim 17 , or a pharmaceutically acceptable salt thereof, wherein X 4  is N, X 5  is CR 8b , and X 6  is CR 8d . 
     
     
         19 . The compound of  claim 17 or 18 , or a pharmaceutically acceptable salt thereof, wherein R 8b , R 8c , R 8d , and R 8e  are each independently hydrogen, halogen, or optionally substituted C 1 -C 8  alkyl. 
     
     
         20 . The compound of  claim 17 , wherein the compound has the structure of Formula (IV-A): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         each R 9  is independently hydrogen, halogen, CN, NO 2 , OR 5 , SR 5 , N(R 5 )R 6 , C(O)R 5 , C(O)OR 5 , C(O)N(R 5 )R 6 , optionally substituted C 1 -C 8  alkyl, optionally substituted C 1 -C 8  haloalkyl, optionally substituted C 1 -C 8  heteroalkyl, optionally substituted C 1 -C 8  alkoxy, optionally substituted C 1 -C 8  alkylamino, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl; and 
         q 1  is 0, 1, 2, or 3. 
       
     
     
         21 . The compound of  claim 17 , wherein the compound has the structure of Formula (IV-B): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Y 1 , Y 2 , and Y 3  are each independently CR 10 , NR 10a , or N; wherein at least one of Y 1 , Y 2 , and Y 3  is CR 10 ; 
         each R 10  is independently hydrogen, halogen, CN, optionally substituted C 1 -C 8  alkyl, optionally substituted C 1 -C 8  haloalkyl, optionally substituted C 1 -C 8  heteroalkyl, optionally substituted C 1 -C 8  alkoxy, or optionally substituted C 1 -C 8  alkylamino, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl; and 
         each R 10a  is independently hydrogen optionally substituted C 1 -C 8  alkyl, optionally substituted C 1 -C 8  haloalkyl, optionally substituted C 1 -C 8  heteroalkyl, optionally substituted C 1 -C 8  alkoxy, optionally substituted C 1 -C 8  alkylamino, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl. 
       
     
     
         22 . The compound of  claim 21 , or a pharmaceutically acceptable salt thereof, wherein X 4  is N and X 5  is CR 8b . 
     
     
         23 . The compound of  claim 17 , wherein the compound has the structure of Formula (IV-C): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Y 1 , Y 2 , and Y 3  are each independently CR 10 , NR 10a , or N; wherein at least one of Y 1 , Y 2 , and Y 3  is CR 10 ; 
         each R 10  is independently hydrogen, halogen, CN, optionally substituted C 1 -C 8  alkyl, optionally substituted C 1 -C 8  haloalkyl, optionally substituted C 1 -C 8  heteroalkyl, optionally substituted C 1 -C 8  alkoxy, or optionally substituted C 1 -C 8  alkylamino, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl; and 
         each R 10a  is independently hydrogen optionally substituted C 1 -C 8  alkyl, optionally substituted C 1 -C 8  haloalkyl, optionally substituted C 1 -C 8  heteroalkyl, optionally substituted C 1 -C 8  alkoxy, optionally substituted C 1 -C 8  alkylamino, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl. 
       
     
     
         24 . The compound of  claim 23 , or a pharmaceutically acceptable salt thereof, wherein X 4  is N and X 6  is CR 8d . 
     
     
         25 . The compound of  claim 23 , or a pharmaceutically acceptable salt thereof, wherein X 4  is CR 8a  and X 6  is N. 
     
     
         26 . The compound of  claim 17 , wherein the compound has the structure of Formula (IV-D): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Y 1 , Y 2 , and Y 3  are each independently CR 10 , NR 10a , or N; wherein at least one of Y 1 , Y 2 , and Y 3  is CR 10 ; 
         each R 10  is independently hydrogen, halogen, CN, optionally substituted C 1 -C 8  alkyl, optionally substituted C 1 -C 8  haloalkyl, optionally substituted C 1 -C 8  heteroalkyl, optionally substituted C 1 -C 8  alkoxy, or optionally substituted C 1 -C 8  alkylamino, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl; and 
         each R 10a  is independently hydrogen, optionally substituted C 1 -C 8  alkyl, optionally substituted C 1 -C 8  haloalkyl, optionally substituted C 1 -C 8  heteroalkyl, optionally substituted C 1 -C 8  alkoxy, optionally substituted C 1 -C 8  alkylamino, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl. 
       
     
     
         27 . The compound of  claim 26 , or a pharmaceutically acceptable salt thereof, wherein X 4  is N and X 5  is CR 8b . 
     
     
         28 . The compound of  claim 26 , or a pharmaceutically acceptable salt thereof, wherein X 4  is CR 8a  and X 5  is N. 
     
     
         29 . The compound of  claim 26 , or a pharmaceutically acceptable salt thereof, wherein X 4  is N and X 5  is N. 
     
     
         30 . The compound of any one of  claims 21 to 29 , or a pharmaceutically acceptable salt thereof, wherein Y 1  and Y 3  are each independently NR 10a  or N; and Y 2  is CR 10 . 
     
     
         31 . The compound of any one of  claims 21 to 29 , or a pharmaceutically acceptable salt thereof, wherein Y 2  and Y 3  are each independently NR 10a  or N; and Y 1  is CR 10 . 
     
     
         32 . The compound of any one of  claims 21 to 29 , or a pharmaceutically acceptable salt thereof, wherein Y 1  and Y 2  are each independently NR 10a  or N; and Y 3  is CR 10 . 
     
     
         33 . The compound of any one of  claims 1 to 32 , or a pharmaceutically acceptable salt thereof, wherein Z is absent or —O—. 
     
     
         34 . The compound of any one of  claims 1 to 32 , or a pharmaceutically acceptable salt thereof, wherein Z is —NR 1a —. 
     
     
         35 . The compound of  claim 34 , or a pharmaceutically acceptable salt thereof, wherein Z is —NH—. 
     
     
         36 . The compound of any one of  claims 1 to 35 , or a pharmaceutically acceptable salt thereof, wherein:
 L is   
       
         
           
           
               
               
           
         
          wherein 
         Ring B is an optionally substituted 3-7 membered carbocyclyl, or optionally substituted 4-7 membered heterocyclyl; 
         L 1  is absent, or an optionally substituted C 1 -C 10  alkylene or optionally substituted C 1 -C 10  heteroalkylene; and 
         L 2  is absent, or an optionally substituted C 1 -C 10  alkylene, optionally substituted C 2 -C 10  alkenylene, optionally substituted C 2 -C 10  alkynylene, or optionally substituted C 1 -C 10  heteroalkylene. 
       
     
     
         37 . The compound of  claim 36 , or a pharmaceutically acceptable salt thereof, wherein:
 Ring B is an optionally substituted 3-7 membered carbocyclyl;   L 1  is absent or an optionally substituted C 1 -C 10  alkylene; and   L 2  is absent or an optionally substituted C 1 -C 10  alkylene.   
     
     
         38 . The compound of  claim 36 or claim 37 , or a pharmaceutically acceptable salt thereof, wherein:
 L 1  is absent; and   L 2  is C 1 -C 10  alkylene.   
     
     
         39 . The compound of any one of  claims 36 to 38 , or a pharmaceutically acceptable salt thereof, wherein Ring B is an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptyl, spiro[4.4]nonyl, or spiro[3.4]octanyl ring. 
     
     
         40 . The compound of any one of  claims 1 to 39 , or a pharmaceutically acceptable salt thereof, wherein R 2  is halogen, CN, OR 5 , optionally substituted C 1 -C 8  alkyl, optionally substituted C 1 -C 8  alkoxy, optionally substituted C 1 -C 8  alkylamino, optionally substituted C 1 -C 8  haloalkyl, optionally substituted C 1 -C 8  heteroalkyl, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl. 
     
     
         41 . The compound of  claim 40 , or a pharmaceutically acceptable salt thereof, wherein R 2  is an optionally substituted 3-10 membered carbocyclyl. 
     
     
         42 . The compound of any one of  claims 1 to 41 , or a pharmaceutically acceptable salt thereof, wherein R 1  is absent. 
     
     
         43 . The compound of any one of  claims 1 to 41 , or a pharmaceutically acceptable salt thereof, wherein R 1  is oxo (═O). 
     
     
         44 . A pharmaceutical composition comprising a compound of any one of  claims 1 to 43 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         45 . A method for the treatment of abnormal cell growth in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of  claims 1 to 43 , or a pharmaceutically acceptable salt thereof, or the composition of  claim 40 . 
     
     
         46 . The method of  claim 45 , wherein the subject has cancer. 
     
     
         47 . The method of  claim 45 or claim 46 , further comprising administering to the subject a second compound comprising an FLT3 pathway inhibitor, a RAS-RAF-MEK-ERK pathway inhibitor, or a PI3K-AKT-mTOR pathway inhibitor or activator. 
     
     
         48 . The method of  claim 47 , wherein the FLT3 pathway inhibitor is gilteritinib, midostaurin, sorafenib, sunitinib, lestaurtinib, quizartinib, crenolanib or sitravatinib, or a pharmaceutically acceptable salt thereof. 
     
     
         49 . The method of  claim 48 , wherein the FLT3 pathway inhibitor is gilteritinib, or a pharmaceutically acceptable salt thereof. 
     
     
         50 . A compound of any one of  claims 1 to 43 , or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer. 
     
     
         51 . A compound of any one of  claims 1 to 43 , or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of cancer. 
     
     
         52 . A combination comprising a compound of any one of  claims 1 to 43 , or a pharmaceutically acceptable salt thereof, and a second compound comprising an FLT3 pathway inhibitor, a RAS-RAF-MEK-ERK pathway inhibitor, or a PI3K-AKT-mTOR pathway inhibitor or activator. 
     
     
         53 . The combination of  claim 52 , wherein the FLT3 pathway inhibitor is gilteritinib, midostaurin, sorafenib, sunitinib, lestaurtinib, quizartinib, crenolanib or sitravatinib, or a pharmaceutically acceptable salt thereof. 
     
     
         54 . The method of  claim 52 or claim 53 , wherein the FLT3 pathway inhibitor is gilteritinib, or a pharmaceutically acceptable salt thereof.